During Pneumocystis pneumonia (PcP), the number of alveolar macrophages (AMs) falls, impairing the innate immune system. This defect is mainly due to increased rate of apoptosis caused by elevated levels of intracellular polyamines. Preliminary results indicate that the levels of ornithine decarboxylase, antizyme inhibitor, and polyamine oxidase that are involved in polyamine synthesis and catabolism are increased during the infection. Increased expression of antizyme inhibitor (AZI) leads to increased polyamine production and uptake, thus raising intracellular polyamine and reactive oxygen species (ROS) levels. ROS damage the mitochondria of AMs, resulting in apoptosis. The central hypothesis of this project is that preventing the increase in intracellular polyamine levels will improve the vitality of AMs, leading to a more effective organism clearance. The long-term goal of this project is to understand the mechanism of pathogenesis of PcP and to develop methods to prevent AMs from undergoing apoptosis, thus enhancing the ability of the host to defend against the infection. To achieve this goal, the mechanism by which Pneumocystis (Pc) induces AZI over-expression will be determined. Preliminary data suggest that Pc cell wall components stimulate AMs to increase AZI expression. Further investigations will be performed to characterize the role of Pc 2-glucan, the major component of the Pc cell wall, in the induction of AZI over-expression. The possibility that other Pc components, such as major surface glycoprotein or mannan, are involved in Pc-induced AZI over-expression will also be examined, and macrophage receptors that transmit the signal to AMs leading to AZI over-expression will be identified. PUBLIC HEALTH RELEVANCE: Pneumocystis, the most common opportunistic pathogen in AIDS patients, induces alveolar macrophage apoptosis in order to increase its chance of survival and reproduction in immunocompromised hosts. This is achieved by increasing the production and uptake of polyamines thus raising polyamine levels in alveolar macrophages. The proposed research will investigate the mechanisms by which Pneumocystis increases polyamine levels in alveolar macrophages.